Functional Cross-Talk between the α(1)- and β(1)-Adrenergic Receptors Modulates the Rapidly Activating Delayed Rectifier Potassium Current in Guinea Pig Ventricular Myocytes

The rapidly activating delayed rectifier potassium current (I(Kr)) plays a critical role in cardiac repolarization. Although I(Kr) is known to be regulated by both α(1)- and β(1)-adrenergic receptors (ARs), the cross-talk and feedback mechanisms that dictate its response to α(1)- and β(1)-AR activation are not known. In the present study, I(Kr) was recorded using the whole-cell patch-clamp technique. I(Kr) amplitude was measured before and after the sequential application of selective adrenergic agonists targeting α(1)- and β(1)-ARs. Stimulation of either receptor alone (α(1)-ARs using 1 μM phenylephrine (PE) or β(1)-ARs using 10 μM xamoterol (Xamo)) reduced I(Kr) by 0.22 ± 0.03 and 0.28 ± 0.01, respectively. The voltage-dependent activation curve of I(Kr) shifted in the negative direction. The half-maximal activation voltage (V(0.5)) was altered by −6.35 ± 1.53 and −1.95 ± 2.22 mV, respectively, with no major change in the slope factor (k). When myocytes were pretreated with Xamo, PE-induced reduction in I(Kr) was markedly blunted and the corresponding change in V(0.5) was significantly altered. Similarly, when cells were pretreated with PE, Xamo-induced reduction of I(Kr) was significantly attenuated. The present results demonstrate that functional cross-talk between α(1)- and β(1)-AR signaling regulates I(Kr). Such non-linear regulation may form a protective mechanism under excessive adrenergic stimulation.